The Maryland Psychiatric Research Center (MPRC) is a University of Maryland School of Medicine program located on the Spring Grove Hospital campus. From the beginning in 1977, basic and clinical scientists share interest in severe mental illness, translational science and independent and collaborative research. The shared mission and facilities provide an intimacy and focus that has resulted in extensive P50 center support over the past 35 years. This Introduction will focus on the first four years of the Conte Center and the proposed renewal for Years 6-10. Apart from the main substance of this Introduction, we note with pride several special activities and considerations: ? Eight pilot projects supported by Conte and MPRC funds enabled 7 early career scientists to engage in science relevant to the hypothesis. The work produced spin-off grant applications, and each of the scientists is now funded [6 NIH and one NARSAD]; ? The Summer Student Program was a heartwarming success with hundreds of applicants for six slots per year, with geographic, sex and cultural diversity and all completing and presenting projects, clinical and basic. ? The MPRC embraces the Conte Center, and the individuals charged with leadership and authority at the MPRC are also Conte investigators. ? One of the initial projects resulted in hypothesis falsification. While disappointing, it produced a novel finding and new conception and is being carried forward in a R01 framework. ? The transition to the proposed renewal constitutes a shift to mechanism and the potential to facilitate rational therapeutic discovery. ? The proposed projects continue testing the fundamental hypothesis in the context of schizophrenia since this is the source of data to date. It involves deconstructing the clinical syndrome with a focus on impaired cognition. Knowledge gained is likely to be relevant to cognition pathology in a number of mental disorders. Given the relevance to neurodevelopment and long-term functioning, impaired cognition may be the field's most important challenge from both a neuroscience and a public health perspective.